The authors concluded that adjuvant chemotherapy showed marginal efficacy in reducing local, distant and overall recurrence and improving survival in patients with localised resectable soft-tissue sarcoma. Benefits were increased when ifosfamide was added to doxorubicin-based regimes. The absence of study quality details means that the reliability of the authors' conclusions is unclear.

Authors' objectives

To evaluate the efficacy of adjuvant chemotherapy in the treatment of localised resectable soft-tissue sarcomas.

Searching

MEDLINE and EMBASE were searched for articles published in or translated into English between 1997 and April 2007. Search terms were reported. Studies found during the search were combined with those included in a previous systematic review (see Other Publications of Related Interest).

Study selection

Randomised controlled trials (RCT) of adjuvant chemotherapy compared to no chemotherapy in the treatment of localised, resectable soft-tissue sarcomas that assessed local recurrence, distal recurrence, overall recurrence and overall survival were eligible for inclusion. Studies of bone sarcomas, advanced or metastatic disease or paediatric populations were excluded.

Included studies were of patients with soft tissue sarcoma of varying subtypes who underwent localised treatment (surgery with or without radiotherapy) with adjuvant treatment of doxorubicin (alone or in combination with other types of chemotherapy) in doses that ranged from 50mg/m2 to 70mg/m2 per cycle compared to patients who underwent localised treatment only. In five studies, the adjuvant chemotherapy was doxorubicin (50mg/m2 to 90 mg/m2 per cycle) combined with ifosfamide (1,500mg/m2 to 5,000mg/m2 per cycle). Where stated, study duration ranged from one year to 11 years.

Two reviewers independently selected the studies for review. Disagreements were resolved by discussion.

Assessment of study quality

The methodological quality of studies retrieved in the current search was assessed independently by two reviewers who used a 15-item modified version of the Detsky quality scale; disagreements were resolved by discussion. Methodological quality of the studies from the previous review was not assessed.

Data extraction

The number of patients with local recurrence, distal recurrence, both local and distal recurrence, number of deaths and number of patients who survived was extracted for each study.

The authors stated neither how the data were extracted for the review nor how many reviewers performed the data extraction.

Methods of synthesis

Pooled odds ratios (OR) were calculated for risk of recurrence using either fixed-effect or random-effects models depending on whether significant statistical heterogeneity was detected. Hazard ratios (HR) were calculated for risk of mortality. Absolute risk reduction (ARR) was calculated for all outcomes. Subgroup analyses were conducted for doxorubicin-based chemotherapy alone and for doxorubicin chemotherapy combined with ifosfamide. The number of patients needed to be treated (NNT) to reduce the risk in one patient was calculated. Heterogeneity was calculated using the Cochran Q statistic.

Results of the review

Eighteen RCTs were included for review (n=1,929).

Local Recurrence (17 studies n= 1,700): Adjuvant chemotherapy was associated with a significant reduction in the risk of local recurrence compared to localised treatment alone when all studies were combined (OR 0.73, 95% CI 0.56 to 0.94, p=0.02, NNT=25; 17 studies, n=1,700). There was no evidence of significant heterogeneity. However, there was no significant effect when studies of doxorubicin therapy alone and doxorubicin therapy combined with ifosfamide were analysed separately.

Distant and Overall Recurrence (18 studies n=1,747): Both doxorubicin alone (OR 0.69, 95% CI 0.56 to 0.86, p=0.001; 13 studies, n=1,338) and doxorubicin combined with ifosfamide (OR 0.61, 95% CI 0.41 to 0.92, p=0.02; five studies, n=409) were associated with a significant reduction in the risk of distant and overall recurrence. This effect remained when all studies were combined (distant recurrence OR 0.67, 95% CI 0.56 to 0.82, p=0.0001; 18 studies, n=1,747). There was no evidence of significant heterogeneity. The NNT for all studies was 12 for distant recurrence and 10 for overall recurrence.

Survival (18 studies, n=1,929): Doxorubicin combined with ifosfamide was associated with a significant reduction in mortality (HR 0.56, 95% CI 0.36 to 0.86, p=0.01; five studies, n=414). Doxorubicin alone did not significantly change the risk of mortality. The NNT for all studies combined was 17. There was no evidence of significant heterogeneity.

Authors' conclusions

Adjuvant chemotherapy showed marginal efficacy in reducing local, distant and overall recurrence and improving survival in patients with localised resectable soft-tissue sarcoma. The benefits were increased with the addition of ifosfamide to doxorubicin-based regimes, but these needed to be weighed against associated toxicities.

CRD commentary

The review addressed a clear question with well-defined inclusion criteria. The search was restricted to two databases for articles in English, so language and publication biases may have been introduced and relevant data may have been missed. Appropriate methods were taken in the study selection process to minimise reviewer error and bias, though it was unclear whether similar steps were taken in the data extraction processes. The quality of studies retrieved from the current search was assessed and appropriate methods to minimise bias were used. However, the results of this quality assessment were not reported and the studies included from the previous systematic review were not subjected to a validity assessment. As a result, it was not possible to ascertain the quality of included studies and, therefore, reliability of data. Appropriate methods were used to combine data. Statistical heterogeneity was assessed. Given the potential for bias in the review process and the lack of information on study quality, the reliability of the authors' conclusions is unclear.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.